Antibodies with enhanced antibody-dependent cellular cytotoxicity activity, methods of their production and use

Abstract

The invention relates, in part, to antibodies with increased ADCC activity. Methods of producing such antibodies are also provided. The antibodies of the invention are produced in mammary epithelial cells, such as those in a non-human transgenic animal engineered to express and secrete the antibody in its milk. The antibodies or compositions comprising the antibodies can be used to treat disease in which ADCC activity provides a benefit. In one embodiment, therefore, the antibodies or compositions comprising the antibodies can be used to treat cancer, lymphoproliferative disease or autoimmune disease.

I/We claim: 
     
         1 - 42 . (canceled) 
     
     
         43 . A method for enhancing the binding of the Fc region of IgG antibodies to an FcγRIII receptor, the method comprising:
 modifying the glycosylation of the IgG antibodies so that the binding of the Fc region of the antibodies to the FcγRIII receptor is enhanced, 
 wherein the glycosylation is modified by producing the antibodies in mammalian mammary epithelial cells; and selecting antibodies that have enhanced binding of the Fc region of the antibodies to the FcγRIII receptor; 
 wherein at least 40% of the antibodies comprises at least one oligomannose; 
 wherein less than 50% of the antibodies contain fucose; and 
 wherein the mammalian mammary epithelial cells are of a transgenic non-human mammal engineered to express the antibodies in its milk. 
 
     
     
         44 . The method of  claim 43 , wherein the antibodies are of the isotype IgG1 or IgG2. 
     
     
         45 . The method of  claim 43 , wherein the FcγRIII receptor is on monocytes, macrophages or natural killer cells. 
     
     
         46 . The method of  claim 43 , wherein the antibodies are modified such that at least one chain of the antibodies does not contain fucose. 
     
     
         47 . The method of  claim 43 , wherein the antibodies are modified such that at least one chain of the antibodies is oligomannose-containing and non-fucosylated. 
     
     
         48 . The method of  claim 43 , wherein the antibodies comprise carbohydrates including a major carbohydrate and wherein the antibodies are modified such that the major carbohydrate of the antibodies is non-fucosylated. 
     
     
         49 . The method of  claim 43 , wherein the antibodies comprise a major carbohydrate and wherein the antibodies are modified such that the major carbohydrate of the antibodies is a non-fucosylated oligomannose. 
     
     
         50 . The method of  claim 43 , wherein the antibodies comprise a major carbohydrate and wherein the antibodies are modified such that the major carbohydrate of the antibodies is a non-fucosylated Man5. 
     
     
         51 . The method of  claim 43 , wherein the antibodies are modified such that less than 40% of the carbohydrates of the antibody contain fucose. 
     
     
         52 . The method of  claim 43 , wherein the antibodies are modified such that at least 60% of the carbohydrates of the antibodies are a non-fucosylated oligomannose and less than 40% of the carbohydrates of the antibodies are fucose-containing. 
     
     
         53 . The method of  claim 43 , wherein the mammary epithelial cells are cells from a goat, sheep, bison, camel, cow, pig, rabbit, buffalo, horse, rat, mouse or llama. 
     
     
         54 . The method of  claim 43 , wherein the transgenic non-human mammal is a goat, sheep, bison, camel, cow, pig, rabbit, buffalo, horse, rat, mouse or llama. 
     
     
         55 . The method of  claim 43 , wherein the antibodies are chimeric antibodies, humanized antibodies or fully human antibodies. 
     
     
         56 . The method of  claim 43 , wherein the antibodies are full-length antibodies. 
     
     
         57 . The method of  claim 43 , wherein the full-length full length antibodies each comprises a heavy chain and a light chain. 
     
     
         58 . The method of  claim 43 , wherein the antibodies are antibody fragments. 
     
     
         59 . The method of  claim 43 , wherein the antibodies are anti CD137 antibodies. 
     
     
         60 . The method of  claim 43 , further comprising measuring binding of the Fc region of the antibodies to the FcγRIII receptor. 
     
     
         61 . The method of  claim 43 , wherein the selected antibodies comprise carbohydrates and wherein less than 40% of the carbohydrates of the antibodies contain fucose.